Free fatty acids (FFAs) are liberated from
lipoproteins by
lipoprotein lipase (LPL) and enter the adipocyte, where they are reassembled into
triglycerides by
esterifying them onto
glycerol. There is a constant flux of FFAs entering and leaving adipose tissue. In humans, lipolysis (hydrolysis of triglycerides into free fatty acids) is controlled through the balanced control of lipolytic
B-adrenergic receptors and a2A-adrenergic receptor-mediated antilipolysis. Fat cells have an important
physiological role in maintaining triglyceride and free fatty acid levels, as well as determining
insulin resistance. Recent advances in biotechnology have allowed for the harvesting of
adult stem cells from adipose tissue, allowing stimulation of tissue regrowth using a patient's own cells. In addition, adipose-derived stem cells from both human and animals reportedly can be efficiently reprogrammed into
induced pluripotent stem cells without the need for
feeder cells. The use of a patient's own cells reduces the chance of tissue rejection and avoids ethical issues associated with the use of human
embryonic stem cells. A growing body of evidence also suggests that different fat depots (i.e. abdominal, omental, pericardial) yield adipose-derived stem cells with different characteristics. These depot-dependent features include
proliferation rate,
immunophenotype,
differentiation potential,
gene expression, as well as sensitivity to hypoxic culture conditions. Oxygen levels seem to play an important role on the metabolism and in general the function of adipose-derived stem cells. Adipose tissue is a major peripheral source of
aromatase in both males and females, contributing to the production of
estradiol.
Adipose derived hormones include: •
Adiponectin •
Resistin •
Plasminogen activator inhibitor-1 (PAI-1) •
TNFα •
IL-6 •
Leptin •
Estradiol (E2) Adipose tissues also secrete a type of
cytokines (cell-to-cell signalling proteins) called
adipokines (adipose cytokines), which play a role in obesity-associated complications. Perivascular adipose tissue releases adipokines such as adiponectin that affect the contractile function of the vessels that they surround.
Brown fat Brown fat or
brown adipose tissue (BAT) is a specialized form of adipose tissue important for adaptive
thermogenesis in humans and other mammals. BAT can generate heat by "uncoupling" the
respiratory chain of
oxidative phosphorylation within
mitochondria through tissue-specific expression of
uncoupling protein 1 (UCP1). BAT activation may also occur in response to overfeeding. UCP1 activity is stimulated by long chain fatty acids that are produced subsequent to
β-adrenergic receptor activation. UCP1 is proposed to function as a fatty acid proton
symporter, although the exact mechanism has yet to be elucidated. In contrast, UCP1 is inhibited by
ATP,
ADP, and
GTP. Attempts to simulate this process
pharmacologically have so far been unsuccessful. Techniques to manipulate the differentiation of "brown fat" could become a mechanism for
weight loss therapy in the future, encouraging the growth of tissue with this specialized metabolism without inducing it in other organs. A review on the eventual therapeutic targeting of
brown fat to treat human obesity was published by Samuelson and
Vidal-Puig in 2020. Until recently, brown adipose tissue in humans was thought to be primarily limited to infants, but new evidence has overturned that belief. Metabolically active tissue with temperature responses similar to brown adipose was first reported in the neck and trunk of some human adults in 2007, and the presence of brown adipose in human adults was later verified
histologically in the same anatomical regions.
Beige fat and WAT browning Browning of WAT, also referred to as "beiging", occurs when adipocytes within WAT depots develop features of BAT.
Beige adipocytes take on a multilocular appearance (containing several lipid droplets) and increase expression of
uncoupling protein 1 (UCP1). In doing so, these normally energy-storing adipocytes become energy-releasing adipocytes. The calorie-burning capacity of brown and beige fat has been extensively studied as research efforts focus on therapies targeted to treat obesity and diabetes. The drug
2,4-dinitrophenol, which also acts as a chemical
uncoupler similarly to UCP1, was used for weight loss in the 1930s. However, it was quickly discontinued when excessive dosing led to adverse side effects including
hyperthermia and death. Cold is a primary regulator of BAT processes and induces WAT browning. Browning in response to chronic cold exposure has been well documented and is a reversible process. A study in mice demonstrated that cold-induced browning can be completely reversed in 21 days, with measurable decreases in UCP1 seen within a 24-hour period. A study by Rosenwald et al. revealed that when the animals are re-exposed to a cold environment, the same adipocytes will adopt a beige phenotype, suggesting that beige adipocytes are retained. Transcriptional regulators, as well as a growing number of other factors, regulate the induction of beige fat. Four regulators of transcription are central to WAT browning and serve as targets for many of the molecules known to influence this process. These include peroxisome proliferator-activated receptor gamma
(PPARγ),
PRDM16, peroxisome proliferator-activated receptor gamma coactivator 1 alpha
(PGC-1α), and Early B-Cell Factor-2 (EBF2). The list of molecules that influence browning has grown in direct proportion to the popularity of this topic and is constantly evolving as more knowledge is acquired. Among these molecules are
irisin and fibroblast growth factor 21 (
FGF21), which have been well-studied and are believed to be important regulators of browning. Irisin is secreted from muscle in response to exercise and has been shown to increase browning by acting on beige preadipocytes. FGF21, a hormone secreted mainly by the liver, has garnered a great deal of interest after being identified as a potent stimulator of glucose uptake and a browning regulator through its effects on PGC-1α. FGF21 may also be secreted in response to exercise and a low protein diet, although the latter has not been thoroughly investigated. Data from these studies suggest that environmental factors like diet and exercise may be important mediators of browning. In mice, it was found that beiging can occur through the production of
methionine-enkephalin peptides by
type 2 innate lymphoid cells in response to
interleukin 33.
Genomics and bioinformatics tools to study browning Due to the complex nature of adipose tissue and a growing list of browning regulatory molecules, great potential exists for the use of
bioinformatics tools to improve study within this field. Studies of WAT browning have greatly benefited from advances in these techniques, as beige fat is rapidly gaining popularity as a therapeutic target for the treatment of obesity and diabetes.
DNA microarray is a bioinformatics tool used to quantify expression levels of various genes simultaneously, and has been used extensively in the study of adipose tissue. One such study used microarray analysis in conjunction with Ingenuity IPA software to look at changes in WAT and BAT gene expression when mice were exposed to temperatures of 28 and 6 °C. The most significantly up- and downregulated genes were then identified and used for analysis of differentially expressed pathways. It was discovered that many of the pathways upregulated in WAT after cold exposure are also highly expressed in BAT, such as
oxidative phosphorylation,
fatty acid metabolism, and pyruvate metabolism. These two studies demonstrate the potential for the use of microarray in the study of WAT browning. RNA sequencing (
RNA-Seq) is a powerful computational tool that allows for the quantification of RNA expression for all genes within a sample. Incorporating RNA-Seq into browning studies is of great value, as it offers better specificity, sensitivity, and a more comprehensive overview of gene expression than other methods. RNA-Seq has been used in both human and mouse studies in an attempt characterize beige adipocytes according to their gene expression profiles and to identify potential therapeutic molecules that may induce the beige phenotype. One such study used RNA-Seq to compare gene expression profiles of WAT from wild-type
(WT) mice and those overexpressing Early B-Cell Factor-2 (EBF2). WAT from the transgenic animals exhibited a brown fat gene program and had decreased WAT specific gene expression compared to the WT mice. Thus, EBF2 has been identified as a potential therapeutic molecule to induce beiging. Chromatin immunoprecipitation with sequencing (
ChIP-seq) is a method used to identify protein binding sites on DNA and assess
histone modifications. This tool has enabled examination of
epigenetic regulation of browning and helps elucidate the mechanisms by which protein-DNA interactions stimulate the differentiation of beige adipocytes. Studies observing the chromatin landscapes of beige adipocytes have found that adipogenesis of these cells results from the formation of cell specific chromatin landscapes, which regulate the transcriptional program and, ultimately, control differentiation. Using ChIP-seq in conjunction with other tools, recent studies have identified over 30 transcriptional and epigenetic factors that influence beige adipocyte development. In 1995,
Jeffrey Friedman, in his residency at the
Rockefeller University, together with
Rudolph Leibel,
Douglas Coleman et al. discovered the protein
leptin that the genetically obese mouse lacked. Leptin is produced in the white adipose tissue and signals to the
hypothalamus. When leptin levels drop, the body interprets this as a loss of energy, and hunger increases. Mice lacking this protein eat until they are four times their normal size. Leptin, however, plays a different role in diet-induced obesity in rodents and humans. Because adipocytes produce leptin, leptin levels are elevated in the obese. However, hunger remains, and—when leptin levels drop due to weight loss—hunger increases. The drop of leptin is better viewed as a starvation signal than the rise of leptin as a
satiety signal. However, elevated leptin in obesity is known as
leptin resistance. The changes that occur in the hypothalamus to result in leptin resistance in obesity are currently the focus of obesity research. Gene defects in the leptin gene (
ob) are rare in human obesity. , only 14 individuals from five families have been identified worldwide who carry a mutated
ob gene (one of which was the first ever identified cause of genetic obesity in humans)—two families of Pakistani origin living in the UK, one family living in Turkey, one in Egypt, and one in Austria—and two other families have been found that carry a mutated
ob receptor. Others have been identified as genetically partially deficient in leptin, and, in these individuals, leptin levels on the low end of the normal range can predict obesity. Several
mutations of genes involving the
melanocortins (used in brain signaling associated with appetite) and their
receptors have also been identified as causing obesity in a larger portion of the population than leptin mutations.
Epigenetics Different cell types within adipose tissue exhibit distinct DNA methylation patterns. Mature adipocytes and adipose progenitor cells (ASPCs) show a high degree of hypomethylation, affecting more than 50% of their regulatory regions. This hypomethylation is associated with the activation of genes involved in triglyceride synthesis, such as glycerol‑3‑phosphate acyltransferase 1 (GPAM). In contrast, myeloid cells display approximately 73% hypermethylated regions, reflecting an epigenetic program opposite to that of the adipocytic lineage. Overall, there is a direct relationship between DNA demethylation and gene expression, whereby highly expressed genes tend to exhibit low methylation levels. These epigenetic patterns contribute to defining the functional identity of the different cell types within subcutaneous adipose tissue (SAT).
Physical properties Adipose tissue has a density of ~0.9 g/ml. Thus, a person with more adipose tissue will float more easily than a person of the same weight with more
muscular tissue, since muscular tissue has a density of 1.06 g/ml.
Genomic Architecture and Risk of Abdominal Obesity In addition to the visible changes in adipose tissue associated with obesity, recent research indicates that the risk of developing abdominal obesity and cardiometabolic alterations also depends on the 3D organization of the genome in subcutaneous adipose tissue. Single‑cell epigenomic studies have shown that many genetic variants associated with abdominal fat distribution (measured as WHRadjBMI) are preferentially located in active genomic regions of adipocytes. These regions display low levels of DNA methylation and belong to the so‑called A compartment, which is characterized by higher gene activity. These findings suggest that adipocytes in subcutaneous adipose tissue play a key role in mediating the genetic risk associated with abdominal obesity. ==Body fat meter==